The slow healing or lack of healing of both dermal wounds, such as decubitus ulcers, severe burns and diabetic ulcers and eye lesions, such as a dry eye and corneal ulcer, is a serious medical problem, affecting millions of individuals and causing severe pain or death in may patients. Even the healing of surgical wounds is a problem, particularly in aging and diabetic individuals. Although wounds may be quite dissimilar in terms of cause, morphology and tissue affected, they share a common healing mechanism. Each repair process ultimately requires that the correct type of cell migrate into the wound in sufficient numbers to have an effect: macrophages to debride wounds, fibroblasts for the formation of new collagen and other extracellular matrix components in wounds where the extracellular matrix was damaged, capillary endothelial cells to provide the blood supply, and epithelial cells to ultimately cover the wound.
The unwounded dermis owes much of its structure and strength to the interactions of cells with the extracellular matrix. This matrix contains several proteins known to support the attachment of a wide variety of cells. These proteins include fibronectin, vitronectin, thrombospondin, collagens, and laminin. Although fibronectin is found at relatively low concentrations in unwounded skin, plasma fibronectin deposition occurs soon after wounding. When tissue is damaged, the extracellular matrix must be replaced to provide a scaffold to support cell attachment and migration.
In addition to providing a scaffold, extracellular matrices can also direct cellular proliferation and differentiation. An extracellular matrix can, therefore, direct healing of a tissue in such a way that the correct tissue geometry is restored. When applied to wounds, exogenous fibronectin results in increased wound healing, epithelial migration and collagen deposition. However, a number of considerations, including cost, availability, and instability, make fibronectin or other extracellular matrix proteins less than ideal for such treatment. Moreover, being blood derived products, extracellular matrix proteins may be vectors for infectious disease.
In addition to treatment with fibronectin, attempts have also been made to promote healing by providing cell growth factors such as fibroblast growth factor (FGF) or epidermal growth factor (EGF). Such factors will undoutedly become useful in treating wounds, but because they cannot effect the correct geometry of the new tissue, they can lead to an overly vascularized tissue and abnormal healing.
It is now recognized that the binding domain of fibronectin and the other adhesion proteins is localized in the amino acid sequence Arg-Gly-Asp-X (also termed RGD-X, in accordance with the standard one letter abbreviations for the amino acids) wherein X can be various amino acids or substituents such that the peptide has cell adhesion promoting activity. Arg-Gly-Asp containing peptides and their uses are disclosed, for example, in the following issued United States patents and pending patent applications: U.S. Pat. Nos. 4,578,079 and 4,614,517; Ser. Nos. 744,981 and 738,078. From these discoveries, work has progressed in the generation of various Arg-Gly-Asp containing peptides having various specificities for particular cell surface receptors.
There thus exists a need for an effective agent to promote cell migration and attachment to the site of a wound. Preferably, such an agent should be inexpensive, sterile and have long lasting stability and effectiveness. The present invention satisfies these needs and provides related advantages as well.